The present application represents U.S. national stage of international application PCT/SE99/01077 which has an international filing date of Jun. 16, 1999 and which was published in English under Article 21(2) of the PCT on Dec. 29, 1999 as No. 9/67206. The international application claims priority to Swedish application 9802208-0, filed on Jun. 22, 1998.
The present invention is related to novel compounds, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are useful in therapy, and in particular for the treatment of pain.
The xcex4 receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Ligands for the xcex4 receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the xcex4 receptor have also been shown to possess immunomodulatory activities.
The identification of at least three different populations of opioid receptors (xcexc, xcex4 and xcexa) is now well established and all three are apparent in both central and peripheral nervous systems of many species including man. Analgesia has been observed in various animal models when one or more of these receptors has been activated.
With few exceptions, currently available selective opioid xcex4 ligands are peptidic in nature and are unsuitable for administration by systemic routes. Some non-peptidic xcex4 antagonists have been available for some time (see Takemori and Portoghese, 1992, Ann. Rev. Pharmacol. Tox., 32: 239-269. for review). These compounds, e.g. naltrindole, suffer from rather poor (i.e.,  less than 10-fold) selectivity for the xcex4 receptor vs. xcexc receptor binding and exhibit no analgesic activity, a fact which underscores the need for the development of highly selective non-peptidic xcex4 ligands.
Thus, the problem underlying the present invention was to find new analgesics having improved analgesic effects, but also with an improved side-effect profile over current xcexc agonists and potential oral efficacy.
Analgesics that have been identified and are existing in the prior art have many disadvantages in that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that preferred compounds, described within the prior art, show significant convulsive effects when administered systemically.
The problem mentioned above has now been solved by developing novel 1,4-substituted cyclohexyl compounds, as will be described below.
The novel compounds according to the present invention are defined by the general formula I 
wherein
m and n is each and independently an integer of from 0-3, and one or more of the hydrogens in such an alkylene-chain may optionally be substituted by anyone of C1-C6 alkyl C1-C6 alkoxy or hydroxy; or
one or more of the methylene groups may optionally be substituted by a heteroatom such as O, N or S;
R1 is selected from hydrogen, a branched or straight C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C4-C8(alkyl-cycloalkyl) wherein the alkyl is C1-C2 alkyl and the cycloalkyl is C3-C6 cycloalkyl;
R2 is selected from any of
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl C2-C6 alkenyl or C2-C6alkynyl;
(iii) xe2x80x94[(CH2)qxe2x80x94 aryl];
(iv) xe2x80x94((CH2)r-heteroaryl) where the heteroaryl has from 5 to 10 atoms and the heteroatom is selected from any of S, N and O;
xe2x80x83and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; and wherein q and r is each and independently an integer of from 0 to 3;
(v) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O;
xe2x80x83and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(vi) C6-C10 aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
(vii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
or
R1 and R2 may optionally form a heterocyclic ring, which may optionally be saturated or unsaturated;
R3 is selected from anyone of
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
(iii) C6-C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
(iv) heteroaryl-(C5-C10alkyl) where the heteroaryl has from 5 to 10 atoms, the heteroatom being selected from any of S, N and O, and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(v) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(vi) xe2x80x94[C3-C6 cycloalkyl-(CH2)q] wherein q is an integer of from 1 to 3;
R4 is selected from
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
(iii) C6-C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
(iv) heteroaryl-(C5-C10alkyl) where the heteroaryl has from 5 to 10 atoms, the heteroatom being selected from any of S, N and O, and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(v) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O;
xe2x80x83and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(vi) C6-C10 aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
(vii) heteroaryl having from 5 to 10 atoms, the heteroatom being selected from any of S, N and O; wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
R5 is selected from anyone of
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
(iii) C6-C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
(iv) heteoaryl-(C5-C10 alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(v) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(vi) C5-C10 aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
(vii) heteroaryl having from 5 to 10 atoms, the heteroatom being selected from any of S, N and O; wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; 
wherein
R7, R8, R9, R10 and R11 is each and independently selected from
(a) hydrogen;
(b) a straight or branched C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
(c) C6-C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
(d) heteroaryl-(C5-C10alkyl), where the heteroaryl has from 5 to 10 atoms, the heteroatom being selected from any of S, N and O, and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
(e) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O;
xe2x80x83and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(f) C6-C10 aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; 
or
R4 and R5 may optionally form a heterocyclic ring, which may optionally be saturated or unsaturated;
Y is each and independently selected from any of hydrogen, CH3; xe2x80x94(CH2)p1CF3; halogen; C1-C3 alkoxy; hydroxy; xe2x80x94NO2; xe2x80x94OCF3; xe2x80x94CONRaRb; xe2x80x94COORa; xe2x80x94CORa; xe2x80x94(CH2)p2NRaRb; xe2x80x94(CH2)p3CH3, (CH2)p4SORaRb; xe2x80x94(CH2)p5SO2Ra; xe2x80x94(CH2)p6SO2NRa; C4-C8(alkyl-cycloalkyl) wherein alkyl is C1-C2 alkyl and cycloalkyl is C3-C6 cycloalkyl; 1 or 2 heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O; and oxides such as N-oxides or sulfoxides; and wherein
Ra and Rb is each and independently selected from hydrogen, a branched or straight C1-C6 alkyl, C1-C6 alkenyl, C3-C8 cycloalkyl; and wherein
p1, p2, p3, p4, p5 and p6 is each and independently 0, 1 or 2.
Within the scope of the invention are also pharmaceutically acceptable salts of the compounds of the formula (I), as well as isomers, hydrates, isoforms and prodrugs thereof.
Examples of heterocyclic ring systems which ma y be formed by R2and R3 together include but are not limited to azeridine, pyrrolidine, piperidine, azepine, azocine, their hydrogenated or dehydrogenated derivatives, their aminoderivatives and other aza-heterocycle moieties and their derivatives, such as dihydroimidazoles, di-, tetra- and hexahydropyrimidines and the like.
Preferred compounds according to the invention are compounds of the formula I wherein
m=n=1
R1 is selected from hydrogen or C1-C6 alkyl;
R2 is selected from
(i) hydrogen;
(ii) C6-C10 aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above;
(iii) C1-C6 alkyl; or
(iv) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
R3 is selected from
(i) hydrogen;
(ii) C6-C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above;
(iii) xe2x80x94[C3-C6 cycloalkyl-(CH2)q] wherein q is an integer of from 1 to 3;
R4 is hydrogen;
R5 is selected from anyone of
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
(iii) C6-C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above;
(iv) heteroaryl-(C5-C10alkyl) where the heteroaryl has from 5 to 10 atoms, the heteroatom being selected from any of S, N and O, and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
(v) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
(vi) heteroaryl having from 5 to 10 atoms, the heteroatom being selected from any of S, N, and O; wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above; 
wherein
R7, R8, R9, R10 and R11 is each and independently selected from
(a) hydrogen;
(b) a straight or branched C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
(c) C6-C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above;
(d) heteroaryl-(C5-C10alkyl), where the heteroaryl has from 5 to 10 atoms, the heteroatom being selected from any of S, N and O, and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
(e) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
(f) C6-C10 aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above; 
or
R4 and R5 may optionally form a heterocyclic ring, which may optionally be saturated;
Particularly preferred compounds according to the invention are compounds of the formula I wherein
m=n=1
R1 is selected from
(i) hydrogen; and
(ii) methyl;
R2 is selected from
(i) hydrogen;
(ii) phenyl;
(iii) C1-C3 alkyl;
(iv) C3-C6 cycloalkyl;
or
R1 and R2 taken together may form a ring of from 4 to 6 atoms selected from C, N and O;
R3 is selected from
(i) hydrogen;
(ii) xe2x80x94CH2-cyclohexyl;
(iii) xe2x80x94CH2-phenyl, optionally substituted by one or more halogens;
(iv) xe2x80x94CH2-naphthyl;
R4 is hydrogen;
R5 is selected from
(i) hydrogen; 
(iv) heteroaryl-(C5-C10), where the heteroaryl has from 5 to 10 atoms, the heteroatom being selected from any of S, N and O, and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 sustituents Y where each Y is as defined above;
By xe2x80x9chalogenxe2x80x9d we mean chloro, fluoro, bromo and iodo.
By xe2x80x9carylxe2x80x9d we mean an aromatic ring having 6 or 10 carbon atoms, such as phenyl and naphthyl.
By xe2x80x9cheteroarylxe2x80x9d we mean an aromatic ring in which one or more of the from 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
By xe2x80x9cisomersxe2x80x9d we mean compounds of the formula (I), which differ by the position of their functional group and/or orientation. By xe2x80x9corientationxe2x80x9d we mean stereoisomers, diastereoisomers, regioisomers and enantiomers.
By xe2x80x9cisoformsxe2x80x9d we mean compounds of the formula I which differ in the relative physical arrangement of molecules by crystal lattice, such that isoforms refer to various crystalline compounds and amorphous compounds.
By xe2x80x9cprodrugxe2x80x9d we mean pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product of the derivative is an active form of the drug. The reference by Goodman and Gilmans, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, xe2x80x9cBiotransformation of Drugs, p. 13-15, describing prodrugs generally, is hereby incorporated by reference.
The novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive.
Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents.
Compounds of the invention are useful in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
Compounds of the invention are useful for the treatment of diarrhoea, depression, urinary incontinence, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (eg. Amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotica, anxiolytics, neuromuscular blockers and opioids.
The compounds of the present invention in isotopically labelled form are useful as a diagnostic agent.
Also within the scope of the invention is the use of any of the compounds according to the formula (I) above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.
A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula (I) above, is administered to a patient in need of such treatment.
The best mode of performing the invention known at present, is to use the compounds according to Example 1 (compound 7); Example 2 (compound 9); Example 3 (compound 10); and Example 6 (compound 17). The numbering of the compounds is in accordance with the numbering in the Schemes presented in the following.
The compounds of the present invention may be prepared as described in the following.

As shown in SCHEME I above, compounds of the formula (H) may be obtained from compounds of the formula (G), by deprotection by methods known in the art and exemplified in the literature, see e.g. Protecting groups by Green, or Modern Synthetic Reactions by House, which are well known to a person skilled in the art.
As shown in SCHEME I, compounds of the formula (G) may be obtained by reaction among an amine of the formula (F), and using a guanylating reagent, an amidinating reagent or an alkylating reagent. These reactions may be performed in solvents such as THF, toluene, ether, dimethylformamide, dioxane, dichloromethane or in solvents mixtures.
As shown in SCHEME I, compounds of the formula (F) and (H) may be obtained from compounds of the formula (E), by deprotection of the N,N-dibenzyl group by methods known in the art and exemplified in the literature, see, e.g. Protecting groups by Green, Modern Synthetic Reactions by House, March, J., Advanced Organic Chemistry 4th Ed., John Wiley and Sons, 1992, which are well known to a person skilled in the art.
As shown in SCHEME I, compounds of the formula (E) may be obtained from compounds of the formula (D), and reacted with commercially available alkyl isocyanate such as phenyl isocyanate or with dialkylcarbamoyl chloride, prepared by methods known in the art literature (March, J., Advanced Organic Chemistry 4 th Ed., John Wiley and Sons, 1992) or the like in presence of a base such as triethylamine, Na2CO3,K2CO3,K3PO4, CsF, NaOH, DIPEA or the like. The reaction may be carried out in solvents such as THF, dichloromethane, toluene, ether, dimethylformamide, dioxane, or in solvents mixtures.
As shown in SCHEME I, compounds of the formula (D) may be obtained from a reduction of an amide of the formula (C). The reduction step may be performed with a reducing agent commercially available such LiA1H4, BH3, NaBH3CN or the like in the presence of solvent such as THF, dioxane, ether, dichloromethane toluene or in a solvents mixtures.
As shown in the SCHEME I, compounds of the formula (C) may be obtained by reactions among a carbonyl compound of the formula (B) wherein X is a suitable leaving group such as chloro, bromo, hydroxy or the like, and with an alkyl amine such as 2,2-diphenylethylamine and cyclohexanemethylamine or the like. The reaction may be performed in solvents such as THF, toluene, ether, dimethyl-formamide, dioxane, dichloromethane or solvents mixtures.
As shown in SCHEME I, compounds of the formula (B) may be obtained by protecting a commercially available amine compound of the formula (A), by methods known in the art and exemplified in the literature, see e.g. Protecting groups by Green, or Modern Synthetic Reactions by House, followed by acid activation using a chloroformate such as isobutylchloroformate in a solvent such as THF.
In Scheme I above R1, R2, R3, R4, R5 and R5 are as defined in formula I above.

Compounds of the general formula N may be prepared by following the procedure described in Scheme 2 below.
A commercially available cis/trans mixture of 1,4-bis-aminomethyl cyclohexane (compound I) is converted into mono-(diBoc)-guanidinomethyl derivative K using a protected guanylating reagent such as 1-H-pyrazole-1-(N,N-bis(tert-butoxycarbonyl)carboxamidine in an organic solvent such a THF.
The secondary amine (compound L) may be generated using a reductive amination step, where compound K is treated with an aldehyde in the presence of an acid such as acetic acid or ZnCl2 in a protic solvent such as methanol or ethanol in the presence of a reducing agent such as sodium cyanoborohydride.
Compounds of the general formula M may be obtained by performing an urea reaction where compound L is reacted with a dialkylcarbamoyl chloride such as N-methyl-N-phenyl-carbamoylchloride in a solvent such as methylene chloride and in the presence of a tertiary amine such as triethylamine or the like.
Finally, compound of the general formula N may be obtained by cleavage of the Boc protecting groups, using an acid such as trifluoroacetic acid or aqueous hydrochloric acid.
In Scheme I above R1, R2, and R3 are as defined in formula I above.